rs139779505

chr16-2088110-G-Achr16-2088110-G-Cchr16-2088110-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000548.5(TSC2):c.5131G>A(p.Val1711Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,612,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1711L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 2.68

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.06284088).
• BP6: Variant 16-2088110-G-A is Benign according to our data. Variant chr16-2088110-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 64983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088110-G-A is described in Lovd as [Likely_benign]. Variant chr16-2088110-G-A is described in Lovd as [Pathogenic]. Variant chr16-2088110-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.5131G>A	p.Val1711Met	missense_variant	40/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5131G>A	p.Val1711Met	missense_variant	40/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000240 AC: 60 AN: 250396 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135706

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1460614 Hom.: 1 Cov.: 32 AF XY: 0.000179 AC XY: 130 AN XY: 726638

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74490

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	This variant is associated with the following publications: (PMID: 21984974, 22903760, 24631838, 27176796, 22558107, 28088512, 23514105) -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TSC2: BS1, BS2 -

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 27, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 31, 2020	- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.34	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.16	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0070	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.017	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.53
MVP		0.87
ClinPred		0.017	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139779505; hg19: chr16-2138111; COSMIC: COSV51916049; COSMIC: COSV51916049;